scholarly journals LIS1 and DCX: Implications for Brain Development and Human Disease in Relation to Microtubules

Scientifica ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-17 ◽  
Author(s):  
Orly Reiner
Keyword(s):  
Brain Development ◽  
Neuronal Migration ◽  
Place Of Birth ◽  
Microtubule Associated Proteins ◽  
Final Destination ◽  
Brain Malformations ◽  
Wide Range ◽  
Associated Functions ◽  
Associated Proteins ◽  
Neuronal Polarization

Proper lamination of the cerebral cortex requires the orchestrated motility of neurons from their place of birth to their final destination. Improper neuronal migration may result in a wide range of diseases, including brain malformations, such as lissencephaly, mental retardation, schizophrenia, and autism. Ours and other studies have implicated that microtubules and microtubule-associated proteins play an important role in the regulation of neuronal polarization and neuronal migration. Here, we will review normal processes of brain development and neuronal migration, describe neuronal migration diseases, and will focus on the microtubule-associated functions of LIS1 and DCX, which participate in the regulation of neuronal migration and are involved in the human developmental brain disease, lissencephaly.

scholarly journals The structured core of human β tubulin confers isotype-specific polymerization properties

2016 ◽  
Vol 213 (4) ◽  
pp. 425-433 ◽  
Author(s):  
Melissa C. Pamula ◽  
Shih-Chieh Ti ◽  
Tarun M. Kapoor
Keyword(s):  
Dynamic Instability ◽  
Sequence Divergence ◽  
Regulatory Proteins ◽  
Microtubule Dynamic ◽  
Microtubule Associated Proteins ◽  
Cytoskeleton Organization ◽  
Wide Range ◽  
Associated Proteins ◽  
And Function ◽  
Β Tubulin

Diversity in cytoskeleton organization and function may be achieved through variations in primary sequence of tubulin isotypes. Recently, isotype functional diversity has been linked to a “tubulin code” in which the C-terminal tail, a region of substantial sequence divergence between isotypes, specifies interactions with microtubule-associated proteins. However, it is not known whether residue changes in this region alter microtubule dynamic instability. Here, we examine recombinant tubulin with human β isotype IIB and characterize polymerization dynamics. Microtubules with βIIB have catastrophe frequencies approximately threefold lower than those with isotype βIII, a suppression similar to that achieved by regulatory proteins. Further, we generate chimeric β tubulins with native tail sequences swapped between isotypes. These chimeras have catastrophe frequencies similar to that of the corresponding full-length construct with the same core sequence. Together, our data indicate that residue changes within the conserved β tubulin core are largely responsible for the observed isotype-specific changes in dynamic instability parameters and tune tubulin’s polymerization properties across a wide range.

scholarly journals Heterogeneity of Microtubule-Associated Proteins and Brain Development

1982 ◽  
Vol 129 (2) ◽  
pp. 465-471 ◽  
Author(s):  
Jacques FRANCON ◽  
Ana Maria LENNON ◽  
Arlette FELLOUS ◽  
Alain MARECK ◽  
Michel PIERRE ◽  
...  
Keyword(s):  
Brain Development ◽  
Microtubule Associated Proteins ◽  
Associated Proteins

scholarly journals Erratum to: Novel function of PIWIL1 in neuronal polarization and migration via regulation of microtubule-associated proteins

2016 ◽  
Vol 9 (1) ◽  
Author(s):  
Ping-ping Zhao ◽  
Mao-jin Yao ◽  
Si-yuan Chang ◽  
Lan-tao Gou ◽  
Mo-fang Liu ◽  
...  
Keyword(s):  
Microtubule Associated Proteins ◽  
Associated Proteins ◽  
And Migration ◽  
Neuronal Polarization

scholarly journals A proteomic survey of microtubule-associated proteins in a R402H TUBA1A mutant mouse

PLoS Genetics ◽  
2020 ◽  
Vol 16 (11) ◽  
pp. e1009104
Author(s):  
Ines Leca ◽  
Alexander William Phillips ◽  
Iris Hofer ◽  
Lukas Landler ◽  
Lyubov Ushakova ◽  
...  
Keyword(s):  
Neuronal Migration ◽  
Molecular Mechanisms ◽  
Mutant Mouse ◽  
Critical Role ◽  
Recurrent Mutation ◽  
Intrinsic Defect ◽  
Quantitative Mass Spectrometry ◽  
Microtubule Associated Proteins ◽  
Associated Proteins ◽  
A Cell

Microtubules play a critical role in multiple aspects of neurodevelopment, including the generation, migration and differentiation of neurons. A recurrent mutation (R402H) in the α-tubulin gene TUBA1A is known to cause lissencephaly with cerebellar and striatal phenotypes. Previous work has shown that this mutation does not perturb the chaperone-mediated folding of tubulin heterodimers, which are able to assemble and incorporate into the microtubule lattice. To explore the molecular mechanisms that cause the disease state we generated a new conditional mouse line that recapitulates the R402H variant. We show that heterozygous mutants present with laminar phenotypes in the cortex and hippocampus, as well as a reduction in striatal size and cerebellar abnormalities. We demonstrate that homozygous expression of the R402H allele causes neuronal death and exacerbates a cell intrinsic defect in cortical neuronal migration. Microtubule sedimentation assays coupled with quantitative mass spectrometry demonstrated that the binding and/or levels of multiple microtubule associated proteins (MAPs) are perturbed by the R402H mutation including VAPB, REEP1, EZRIN, PRNP and DYNC1l1/2. Consistent with these data we show that the R402H mutation impairs dynein-mediated transport which is associated with a decoupling of the nucleus to the microtubule organising center. Our data support a model whereby the R402H variant is able to fold and incorporate into microtubules, but acts as a gain of function by perturbing the binding of MAPs.

Changes in composition and activity of microtubule-associated proteins during brain development

Nature ◽  
1980 ◽  
Vol 284 (5754) ◽  
pp. 353-355 ◽  
Author(s):  
A. Mareck ◽  
A. Fellous ◽  
J. Francon ◽  
J. Nunez
Keyword(s):  
Brain Development ◽  
Microtubule Associated Proteins ◽  
Associated Proteins

scholarly journals Defects in Axonal Elongation and Neuronal Migration in Mice with Disrupted tau and map1b Genes

2000 ◽  
Vol 150 (5) ◽  
pp. 989-1000 ◽  
Author(s):  
Yosuke Takei ◽  
Junlin Teng ◽  
Akihiro Harada ◽  
Nobutaka Hirokawa
Keyword(s):  
Knockout Mice ◽  
Neuronal Migration ◽  
Hippocampal Neurons ◽  
Primary Cultures ◽  
Double Knockout ◽  
Microtubule Organization ◽  
Axonal Elongation ◽  
Microtubule Associated Proteins ◽  
Associated Proteins

Tau and MAP1B are the main members of neuronal microtubule-associated proteins (MAPs), the functions of which have remained obscure because of a putative functional redundancy (Harada, A., K. Oguchi, S. Okabe, J. Kuno, S. Terada, T. Ohshima, R. Sato-Yoshitake, Y. Takei, T. Noda, and N. Hirokawa. 1994. Nature. 369:488–491; Takei, Y., S. Kondo, A. Harada, S. Inomata, T. Noda, and N. Hirokawa. 1997. J. Cell Biol. 137:1615–1626). To unmask the role of these proteins, we generated double-knockout mice with disrupted tau and map1b genes and compared their phenotypes with those of single-knockout mice. In the analysis of mice with a genetic background of predominantly C57Bl/6J, a hypoplastic commissural axon tract and disorganized neuronal layering were observed in the brains of the tau+/+map1b−/− mice. These phenotypes are markedly more severe in tau−/−map1b−/− double mutants, indicating that tau and MAP1B act in a synergistic fashion. Primary cultures of hippocampal neurons from tau−/−map1b−/− mice showed inhibited axonal elongation. In these cells, a generation of new axons via bundling of microtubules at the neck of the growth cones appeared to be disturbed. Cultured cerebellar neurons from tau−/−map1b−/− mice showed delayed neuronal migration concomitant with suppressed neurite elongation. These findings indicate the cooperative functions of tau and MAP1B in vivo in axonal elongation and neuronal migration as regulators of microtubule organization.

scholarly journals Identification of disease-relevant modulators of the SHH pathway in the developing brain

Development ◽  
2021 ◽  
Vol 148 (17) ◽  
Author(s):  
Nora Mecklenburg ◽  
Izabela Kowalczyk ◽  
Franziska Witte ◽  
Jessica Görne ◽  
Alena Laier ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Modifier Genes ◽  
Microtubule Associated Proteins ◽  
Shh Pathway ◽  
Brain Malformations ◽  
Associated Proteins ◽  
Positive Regulators ◽  
Functional Analyses ◽  
The Brain ◽  
Variable Penetrance

ABSTRACT Pathogenic gene variants in humans that affect the sonic hedgehog (SHH) pathway lead to severe brain malformations with variable penetrance due to unknown modifier genes. To identify such modifiers, we established novel congenic mouse models. LRP2-deficient C57BL/6N mice suffer from heart outflow tract defects and holoprosencephaly caused by impaired SHH activity. These defects are fully rescued on a FVB/N background, indicating a strong influence of modifier genes. Applying comparative transcriptomics, we identified Pttg1 and Ulk4 as candidate modifiers upregulated in the rescue strain. Functional analyses showed that ULK4 and PTTG1, both microtubule-associated proteins, are positive regulators of SHH signaling, rendering the pathway more resilient to disturbances. In addition, we characterized ULK4 and PTTG1 as previously unidentified components of primary cilia in the neuroepithelium. The identification of genes that powerfully modulate the penetrance of genetic disturbances affecting the brain and heart is likely relevant to understanding the variability in human congenital disorders.

Microtubule-associated proteins (MAPs) regulate cAMP signalling through exchange protein directly activated by cAMP (EPAC)

2005 ◽  
Vol 33 (6) ◽  
pp. 1327-1329 ◽  
Author(s):  
S.J. Yarwood
Keyword(s):  
Therapeutic Benefit ◽  
Microtubule Associated Proteins ◽  
Camp Signalling ◽  
Substrate Protein ◽  
Signalling Molecule ◽  
Wide Range ◽  
Associated Proteins ◽  
Pharmaceutical Agents ◽  
Exchange Protein ◽  
In Cells

cAMP is an essential signalling molecule whose concentration in cells is regulated by a wide range of hormones. A large number of diseases, including cancer and asthma, are linked to improper regulation of the cAMP signalling system, and manipulation of cAMP levels by pharmaceutical agents has proven therapeutic benefit. The action of cAMP in cells is mediated through the signalling enzymes PKA (protein kinase A) and EPAC (exchange protein directly activated by cAMP). The study of the function of these proteins is essential to understand the role of cAMP in controlling disease. We have found that EPAC interacts with an ancillary protein, called LC2 (light chain 2), and this interaction enhances EPAC's ability to activate its substrate protein, Rap1 GTPase. This is an important finding because Rap1 is involved in the control of cell migration and cell shape, functions that are disrupted in diseases like cancer. LC2 appears to enhance EPAC activity towards Rap1 by increasing the ability of EPAC to interact with cAMP, so that EPAC activation occurs at lower concentrations of cAMP. The design of inhibitors that disrupt or enhance EPAC1–LC2 interaction may therefore form the basis of future therapeutics for diseases where cAMP signalling through Rap1 is improperly regulated.

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